CASE REPORT
ATRIOVENTRICULAR BLOCK WITH METOPROLOL AND PAROXETINE
Complete Atrioventricular Block Associated With Concomitant Use
of Metoprolol and Paroxetine
ORHAN ONALAN, MD; BIRGUL ELBOZAN CUMURCU, MD; AND LUTFU BEKAR, MD
A 63-year-old woman, who had been treated with 20 mg of
paroxetine and 0.5 mg of alprazolam daily for 1 year and with 50
mg of metoprolol daily for 15 days, presented to a facility else-
where with presyncope and complete atrioventricular block. Three
days after her initial presentation and cessation of metoprolol
treatment, she was transferred to our clinic to be considered for
permanent pacemaker implantation. Paroxetine treatment was
discontinued on day 1 and atrioventricular block resolved on day
5, which was confirmed with a 24-hour Holter recording. No
bradyarrhythmia was induced with similar doses of either meto-
prolol or paroxetine alone. At 2- and 3-year follow-up, the patient
was still free of bradyarrhythmia documented with electrocardiog-
raphy and 24-hour Holter recordings. To our knowledge, we report
the first case of complete atrioventricular block associated with
coadministration of paroxetine and metoprolol. Increasing physi-
cians’ awareness of drug-induced severe bradyarrhythmia might
prevent unnecessary implantation of permanent pacemakers.
Mayo Clin Proc. 2008;83(5):595-599
AV = atrioventricular; AUC = area under the curve; CYP2D6 =
cytochrome P450 2D6; ECG = electrocardiography; SSRI = selective
serotonin reuptake inhibitor
A 63-year-old woman with a history of hypertension
and depression, who had been treated with 20 mg of
paroxetine and 0.5 mg of alprazolam daily for 1 year and
with 50 mg of metoprolol daily for 15 days, presented to a
facility elsewhere with presyncope and complete atrio-
ventricular (AV) block. Three days after her initial pres-
entation and cessation of metoprolol treatment, she was
transferred to our clinic to be considered for implantation
of a permanent pacemaker. At presentation she was asymp-
tomatic: blood pressure was 110/70 mm Hg, heart rate was
40 beats/min, and 12-lead electrocardiography (ECG)
showed complete AV block with a narrow QRS escape
rhythm of 40 beats/min (Figure, A). Results of all diagnostic
tests, including cardiac enzymes, complete blood cell
count, renal function test, electrolytes, thyroid function
tests, chest radiography, and echocardiography, were
normal, and the coronary angiogram was unremarkable.
From the Department of Cardiology (O.O., L.B.) and Department of Psychiatry
(B.E.C.), Gaziosmanpasa University Faculty of Medicine, Tokat, Turkey.
Individual reprints of this article are not available. Address correspondence to
Orhan Onalan, MD, Gaziosmanpasa University Faculty of Medicine, Depart-
ment of Cardiology, Sivas St, 60200, Tokat, Turkey (oonalan@gmail.com).
© 2008 Mayo Foundation for Medical Education and Research
Mayo Clin Proc. • May 2008;83(5):595-599
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
We thought that AV block could be associated with co-
administration of paroxetine and metoprolol. Therefore, we
referred the patient to the psychiatry department, and the
paroxetine treatment was discontinued on day 1. The AV
block completely resolved on day 5 (Figure, B and C), which
was confirmed with a 24-hour Holter recording. Metoprolol
therapy (50 mg/d) was reinstated on day 6, and the patient
was closely monitored for bradyarrhythmia for the next 5
days. No bradyarrhythmia was seen during this period (Fig-
ure, D and F). Metoprolol treatment was discontinued on
day 10, and the patient was discharged with alprazolam (0.5
mg/d), acetylsalicylic acid (100 mg/d), and amlodipine (5
mg/d) on day 12 (Figure, F). One week (Figure, G) and 2
weeks (Figure, H) after hospital discharge, the patient was
still free of bradyarrhythmia. Two weeks after hospital dis-
charge, the patient visited the psychiatry department for con-
sultation. Alprazolam was discontinued, and paroxetine was
reinstated at 10 mg/d and gradually increased to 20 mg/d. A
24-hour Holter recording, performed 3 weeks after hospital
discharge, was normal. At the patient’s 2-year follow-up, the
absence of bradyarrhythmia was documented by means of
12-lead ECG (Figure, I) and 24-hour Holter recording. At
that time the patient was still receiving paroxetine treatment
of 20 mg/d. At the latest available follow-up, performed on
April 26, 2007, the patient was taking clonazepam,
escitalopram, diltiazem, and acetylsalicylic acid, and again
was shown to be free of bradyarrhythmia by ECG (Figure, J)
and a 24-hour Holter recording.
DISCUSSION
We have several reasons to conclude that AV block in this
case was associated with coadministration of metopro-
lol and paroxetine. First, the patient was asymptomatic
while she received paroxetine and alprazolam treatment
alone and presented with presyncope and complete AV
block after taking metoprolol. Second, discontinuation
of metoprolol treatment alone for 3 days did not restore
normal rhythm, but complete recovery was observed after
discontinuation of paroxetine. Third, and most important,
similar doses of either metoprolol or paroxetine alone
induced no bradyarrhythmia.
Metoprolol, a widely prescribed cardioselective β-
blocker, is extensively metabolized in the liver through O-
• www.mayoclinicproceedings.com 595
ATRIOVENTRICULAR BLOCK WITH METOPROLOL AND PAROXETINE
FIGURE. Electrocardiography (lead 1) at admission (A), during the hospital stay (B, C, D, E, and F),
1 week (G) and 2 weeks (H) after hospital discharge, and at 2-year (I) and 3-year (J) follow-up.
demethylation, α-hydroxylation, and N-dealkylation. In
vitro studies have shown that α-hydroxylation of meto-
prolol is mediated by cytochrome P450 2D6 (CYP2D6)
almost completely, and O-demethylation of metoprolol is
mediated by CYP2D6 partially.1 Thus, CYP2D6 mediates
an estimated 70% of metoprolol’s metabolism.2 Selective
serotonin reuptake inhibitors (SSRIs) might interfere with
the metabolism of metoprolol by inhibiting CYP2D6.3
Among SSRIs, paroxetine is one of the most potent
CYP2D6 inhibitors.4 In a study of 8 healthy male volun-
teers, Hemeryck et al4 investigated the effect of multiple-
dose paroxetine intake on the stereoselective pharmacoki-
netics and pharmacodynamics of metoprolol. Volunteers
were given a single oral dose of racemic metoprolol (100
mg) before and after paroxetine treatment (20 mg/d) for 6
days. Paroxetine treatment increased the mean area under
the curve (AUC) of (R)- and (S)-metoprolol significantly
(from 169 to 1340 ng · h/mL; P<.001 for [R]-metoprolol
and from 279 to 1418 ng · h/mL; P<.001 for [S]-met-
oprolol), approximately doubling both maximum plasma
concentration and terminal elimination half-life. In addi-
tion, Hemeryck et al4 observed a significant decrease in the
(S)/(R) AUC ratio and a significant increase in the mean
metoprolol metabolic ratio. The AUC of the metoprolol-
induced decrease in exercise heart rate vs time curve in-
creased by 46% (P<.01) after multiple-dose paroxetine
596 Mayo Clin Proc. • May 2008;83(5):595-599
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
intake, suggesting a more sustained β-blockade. Therefore,
it is likely that long-term pretreatment with paroxetine in
this case greatly reduced metoprolol metabolism and en-
hanced its negative effect on the AV node.
We searched 5 electronic databases for smiliar reports.
The search was carried out using the following electronic
databases from the earliest possible dates through August
2007: (1) MEDLINE; (2) EMBASE; (3) Cochrane Central
Register of Controlled Trials (CCTR); (4) Cumulative
Index to Nursing & Allied Health Literature (CINAHL);
and (5) HealthSTAR. No language, date, or other
restrictions were applied. The following strategy was used
to search all these databases; capitalized terms are con-
trolled: (1) ARRHYTHMIA/; (2) HEART BLOCK/; (3)
BRADYCARDIA/; (4) ANTIDEPRESSIVE AGENTS/; (5)
ANTIDEPRESSANT AGENT/; (6) ANTI-ANXIETY
AGENTS/; (7) ANTIANXIETY AGENTS; (8) ANXIOLYTIC
AGENT/; (9) paroxetine; (10) alprazolam; (11) or/1-3; (12)
or/4-10; (13) and/11-12. Additional publications were
examined using the reference lists of identified papers and
published reviews. Overall, of 1477 initial hits, 3 cases
of bradyarrhythmia associated with coadministration of
SSRIs and β-blockers were identified.5-7 Konig et al5
reported the first case of bradycardia after coadministration
of paroxetine and metoprolol. Walley et al6 described a
case of symptomatic bradycardia with coadministration of
• www.mayoclinicproceedings.com

metoprolol and fluoxetine, another potent inhibitor of
CYP2D6, in a 54-year-old man with a history of coronary
bypass surgery. In this case, the patient’s heart rate was
64 beats/min with metoprolol treatment (100 mg/d) alone.
On the second day of adding fluoxetine treatment (20
mg/d), the patient developed symptomatic bradycardia
(36 beats/min). His heart rate returned to its previous rate
during the next 5 days after fluoxetine treatment was
discontinued. Coadministration of fluoxetine and sotalol in
this case did not cause bradyarrhythmia. Pae et al7 reported
sinus bradycardia (40 beats/min) and sinus pause (4 seconds)
with syncope on the 20th day of paroxetine coadministration
(up to 30 mg/d) in a 78-year-old woman who was receiving
carvedilol (12.5 mg/d) treatment. The patient had no
bradyarrhythmia while receiving carvedilol alone before
paroxetine administration. Normal heart rate was regained
within 5 days after discontinuation of carvedilol and
paroxetine therapy. Bradyarrhythmia had not recurred after
substitution of paroxetine with mirtazapine in addition to
daily treatment with 12.5 mg of carvedilol.
Selective serotonin reuptake inhibitors, without con-
comitant use of β-blocker therapy, were also reported to be
associated with bradyarrhythmia in 5 case reports.8-12 Er-
furth et al8 reported bradycardia in 2 cases after paroxetine
administration. In a 65-year-old patient with a history of
hemorrhagic stroke and depression, severe symptomatic
bradycardia (34-40 beats/min) developed after the third
dose of paroxetine (10 mg/d) and resolved quickly after
intravenous administration of atropine (0.5 mg). In a 51-
year-old patient with a history of bipolar affective disorder,
asymptomatic bradycardia developed after the third dose of
paroxetine treatment (10 mg/d). In this case, the heart rate
was normal 13 days after cessation of paroxetine treatment.
Rothenhausler et al9 reported a case of sinus bradycardia
with syncope in a 32-year-old patient who ingested a total
of 800 mg of citalopram to attempt suicide. Therapeutic
doses of citalopram have also been associated with symp-
tomatic10 and asymptomatic bradycardia.11,12 In addition,
Gambassi et al13 described a case of various AV blocks
(first-degree and Mobitz type I) associated with citalopram,
which were reversed after discontinuation of the drug.
Citalopram can impair AV conduction by inhibiting L-type
calcium-channel current.14
Bupropion, a non–tricyclic antidepressant drug, is an
increasingly prescribed aid in smoking cessation. Bupro-
pion inhibits CYP2D6 and therefore can impair metabo-
lism of drug substrates of this enzyme. McCollum et al15
reported a case of bradycardia in a 56-year-old man when
bupropion (150 mg twice daily) was added to metoprolol
(75 mg twice daily) and diltiazem (240 mg twice daily)
treatment. The patient in this case developed bradycardia
with an atrial rate of 40 beats/min and a junctional escape
Mayo Clin Proc. • May 2008;83(5):595-599
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ATRIOVENTRICULAR BLOCK WITH METOPROLOL AND PAROXETINE
rhythm of 43 beats/min. The patient was admitted to the
hospital, and all 3 medications were withheld. The next
morning, all symptoms had resolved and normal sinus
rhythm returned.
Ahmed et al16 reported a case of sinus bradycardia with
concomitant use of fluoxetine and pimozide. We found 2
cases of bradyarrhythmia associated with alprazolam
use.17,18 Tollefson et al17 described a case of digitalis in-
toxication when alprazolam was added to ongoing digoxin
therapy. Reduced renal clearance of digoxin was postulated
as the mechanism for this interaction. Mullins18 reported a
case of first-degree AV block in a patient with alprazolam
overdose (12 mg). Weak calcium-channel blocker activity
of benzodiazepines could be responsible for this effect.
These data suggest that development of complete AV
block in our case is related to alprazolam use. However, the
alprazolam dose in our case was very small (0.5 mg/d)
and we did not stop alprazolam treatment during the
patient’s hospital stay. Further, it should be noted that in
our case the AV block disappeared despite ongoing alpra-
zolam treatment.
Metoprolol has proven to be effective in the treatment of
coronary artery disease, hypertension, and chronic heart fail-
ure.19-22 Depression is the most common psychiatric illness
and is frequently present in patients with cardiovascular
disease. Selective serotonin reuptake inhibitors are consid-
ered relatively safer than other antidepressants for cardiac
patients.23 Thus, SSRIs are often prescribed to cardiac
patients, and physicians should be aware of serious drug
interactions caused by inhibition of CYP2D6. Paroxetine
currently is among the most widely coprescribed drugs in
patients receiving a CYP2D6 subtrate.24 A study from Nor-
way investigated how frequently CYP2D6 inhibitors are
coadministered with substrates of the enzyme and reported
that the CYP2D6 substrate metoprolol together with a
CYP2D6 inhibitor paroxetine was one of the most fre-
quently prescribed combinations.24
In a randomized placebo-controlled study,25 potential
interactions between carvedilol and fluoxetine were evalu-
ated. Fluoxetine (20 mg) or matching placebo was adminis-
tered to 10 patients with heart failure who were previously
identified as extensive metabolizers of CYP2D6 sub-
strates.25 Patients were maintained on a carvedilol dose of
25 or 50 mg twice daily and given fluoxetine or a placebo
for a minimum of 28 days. Administration of fluoxetine, a
potent CYP2D6 inhibitor, resulted in a stereospecific inhi-
bition in carvedilol metabolism without significantly af-
fecting blood pressure, heart rate, or heart rate variability.
Goryachkina et al26 noted a pronounced inhibition of
metoprolol metabolism when paroxetine (20 mg/d) was
coadministered to 17 depressed patients with acute myo-
cardial infarction. 26 They found mean metoprolol concen-
• www.mayoclinicproceedings.com 597
ATRIOVENTRICULAR BLOCK WITH METOPROLOL AND PAROXETINE
tration AUC increased by 400% and mean α-hydroxy met-
oprolol concentration AUC decreased by approximately
75%. Although no serious adverse effects were noted, 2
patients required a reduction of metoprolol dose because of
excessive bradycardia and severe orthostatic hypotension.
Goryachkina et al suggest that the metoprolol dose be
adjusted when paroxetine is initiated and withdrawn.
Because of polymorphism of the CYP2D6 gene,
CYP2D6 activity varies markedly among individuals.
Consequently, after short-term administration, metoprolol
plasma concentrations were found to be 3- to 10-fold
higher in poor metabolizers than in extensive metab-
olizers.27,28 Accordingly, the decrease in heart rate is greatly
pronounced in poor metabolizers.29,30 The effect of the
CYP2D6 genotype on metoprolol plasma concentrations
persists during long-term treatment; poor metabolizers
have steady-state concentrations that are several times
higher.31 Some suggest that poor metabolizers are more
susceptible to adverse effects than extensive metabolizers
at standard doses of metoprolol.29,32 Consistent with this
suggestion, Wuttke et al33 observed predominantly poor
metabolism of CYP2D6 in patients with serious met-
oprolol-associated adverse events. These findings suggest
that simultaneous administration of potent inhibitors of
CYP2D6 and metoprolol can lead to serious adverse effects
among poor metabolizers.
Sex-related differences in the pharmacokinetics of
metoprolol can cause greater drug exposure in women.34
Thurmann et al35 investigated potential sex differences in
adverse drug reactions caused by β-blockers. The number
of adverse drug reactions associated with the use of
CYP2D6-dependent β-blockers (metoprolol, carvedilol,
nebivolol, and propranolol) was significantly higher in
women than in men (P=.006), whereas frequencies for the
CYP2D6-independent β-blockers (atenolol, sotalol, and
bisoprolol) were not significantly different between men
and women (P>.05). Further, 75% of patients with serious
metoprolol-associated adverse events reported in the
study of Wuttke et al33 were women, and most were poor
metabolizers. Independently of CYP2D6 genotype, women
exhibit significantly higher metoprolol and propranolol
plasma concentrations than men.36
Finally, depression associated with cardiovascular dis-
ease is particularly prevalent in elderly patients.37,38 The
cardiac safety profiles of antidepressants in this population
should be noted because patients might be particularly
vulnerable to adverse effects of drugs and often receive
multiple concomitant medications.
The present case demonstrates that complete AV block
can develop when paroxetine and metoprolol are pre-
scribed together in susceptible patients, such as older
patients, women, and poor metabolizers of metoprolol.
598 Mayo Clin Proc. • May 2008;83(5):595-599
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Thus, heart rate should be closely monitored when these
2 drugs are used together in such patients. Alternatively,
metoprolol can be substituted with atenolol or bisoprolol,
which are not metabolized via CYP2D6-dependent path-
ways. In a patient with a specific indication for meto-
prolol, substitution of paroxetine with an alternative anti-
depressant or reduction of metoprolol dose should be
considered.
CONCLUSION
To our knowledge, we report the first case of complete AV
block associated with coadministration of paroxetine and
metoprolol. Metoprolol, even in relatively small doses, can
lead to severe bradyarrhythmia when coadministered with
therapeutic doses of paroxetine, particularly in susceptible
populations. Increasing physicians’ awareness of drug-in-
duced severe bradyarrhythmia might prevent unnecessary
implantation of permanent pacemakers.
We gratefully acknowledge Maria Lukomsky, for her significant
contribution of expertise in English to this study.
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